3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症临床特点及基因变异分析

doi:10.12372/jcp.2023.22e0624

临床儿科杂志 ›› 2023, Vol. 41 ›› Issue (4): 278-283.doi: 10.12372/jcp.2023.22e0624

3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症临床特点及基因变异分析

常国营¹, 凌诗颖², 邱文娟², 张惠文², 梁黎黎², 顾学范², 韩连书²()

1.上海交通大学医学院附属上海儿童医学中心内分泌遗传代谢科（上海 200127）
2.上海交通大学医学院附属新华医院上海市儿科医学研究所小儿内分泌遗传科（上海 200092）

收稿日期:2022-05-05 出版日期:2023-04-15 发布日期:2023-04-07
通讯作者: 韩连书 E-mail:hanlianshu@xinhuamed.com.cn

Clinical and genetic analysis of children with 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency

CHANG Guoying¹, LING Shiying², QIU Wenjuan², ZHANG Huiwen², LIANG Lili², GU Xuefan², HAN Lianshu²()

1. Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
2. Department of Pediatric Endocrinology and Genetics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

Received:2022-05-05 Online:2023-04-15 Published:2023-04-07
Contact: HAN Lianshu E-mail:hanlianshu@xinhuamed.com.cn

摘要/Abstract

摘要：

目的了解3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症的临床特点及基因变异情况。方法分析6例3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症患儿的临床资料及基因检测结果。结果 6例患儿，男性3例，女性3例。1例家族史阳性。3例患儿当地医院行新生儿筛查提示该疾病，2例患儿为发病后临床诊断，1例患儿至今未发病。5例患儿发病年龄10天~5岁。初诊年龄为1个月~7岁，发病时均有不同程度的代谢危象、低血糖和高乳酸血症等表现。2例患儿死亡。血串联质谱显示3-羟基异戊酰肉碱升高，部分患儿伴有己二酰肉碱升高；尿有机酸分析提示3-羟基-3-甲基戊二酸显著升高，伴3-甲基戊烯二酸、3-羟基异戊酸等增高。4例患儿基因检测均发现HMGCL基因变异：2例c.122G>A（p.R41Q）纯合；1例c.697C>T（p.H233Y）纯合；1例c.145-2A>G和c.590G>A（p.C197Y）复合杂合。其中，c.697C>T（p.H233Y）、c.145-2A>G和c.590G>A（p.C197Y）变异均为首次报道，蛋白结构预测均为可能有害，ACMG评级为可能致病。另2例患儿未行基因检测。结论 3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症临床表型多样，结合血串联质谱、尿有机酸分析及基因诊断可确诊。对3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症的筛查有助于早期确诊及合理治疗。

关键词: 3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症, HMGCL基因, 3-羟基异戊酰肉碱, 3-羟基-3甲基戊二酸

Abstract:

Objective To analyze the clinical characteristics and gene variation for children with 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency (HMGCLD). Methods The clinical data and genetic sequencing results of children with HMGCLD were analyzed. Results There were 6 patients (3 boys and 3 girls). One patient had a positive family history. Neonatal screening in the local hospital indicated HMGCLD in 3 patients, 2 patients were clinically diagnosed after the onset of the disease, and 1 patient remained disease-free. The onset age of 5 patients ranged from 10 days to 5 years and the age of first diagnosis ranged from 1 month to 7 years. There were metabolic crisis, hypoglycemia and hyperlactatemia in different degrees at the onset of the disease. Two patients died. Blood tandem mass spectrometry showed an increase in 3-hydroxyisovaleryl carnitine (C5-OH), and some of the children were accompanied by an increase in hexanedioyl carnitine (C6DC). Urine organic acid analysis showed that 3-hydroxy-3-methylglutaric acid increased significantly, along with 3-methylpentene acid and 3-hydroxyisovaleric acid. The HMGCL gene variation was found in 4 patients. Two patients had a homozygous variation of c.122G>A (p.R41Q), 1 patient had a homozygous variation of c.697C>T (p.H233Y) and 1 patient had a complex heterozygous variation of c.145-2A>G and c.590G>A (p.C197Y). Among them, c.697C>T (p.H233Y), c.145-2A>G, and c.590G>A (p.C197Y) were all reported for the first time. Protein structure was predicted to be potentially harmful, and the grade of ACMG was likely pathogenic. The other two children did not undergo genetic testing. Conclusions The clinical phenotype of HMGCLD is diverse, which can be confirmed by combining blood tandem mass spectrometry, urine organic acid analysis and gene diagnosis. Screening of HMGCLD is helpful for early diagnosis and reasonable treatment.

Key words: 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency, HMGCL gene, 3-hydroxyisovaleryl carnitine, 3-hydroxy-3-methylglutaric

常国营, 凌诗颖, 邱文娟, 张惠文, 梁黎黎, 顾学范, 韩连书. 3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症临床特点及基因变异分析[J]. 临床儿科杂志, 2023, 41(4): 278-283.

CHANG Guoying, LING Shiying, QIU Wenjuan, ZHANG Huiwen, LIANG Lili, GU Xuefan, HAN Lianshu. Clinical and genetic analysis of children with 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency[J]. Journal of Clinical Pediatrics, 2023, 41(4): 278-283.

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参考文献 19

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病例	性别	起病年龄	初诊	是否新筛	家族史	临床表现	血C5-OH	尿3-羟基-3-甲基戊二酸	其他指标	HMGCL 基因变异	随访情况
1	男	2岁	出生	是	无	急性期（抽搐、呕吐、反应差）、智力发育正常	2.02	182	C6DC 0.05，3-MGA 101.92，3-羟基异戊酸255.2，ALT 7000 U·L^-1、AST 7000 U·L^-1、高乳酸	未做	现11岁，生长发育可，成绩一般
2	男	5岁	7岁	否	无	精神发育迟滞、记忆力差、抽搐	3.16	106	C6DC 0.07，3-MGA 252.7，3-羟基异戊酸89，ALT158，高乳酸、低血糖	c.122G>A (p.R41Q)纯合	现10岁8个月，成绩不及格
3	男	10日龄	3月龄	否	有	急性期（拒奶、呕吐、反应差）、智力发育正常	3.04	803.6	C6DC 0.21，3-MGA 504.5，3-羟基异戊酸549.8，ALT 100 U·L^-1，乳酸、血氨正常	c.122G>A (p.R41Q)纯合	现1岁，生长发育可
4	女	1月龄	1月龄	否	无	急性期（纳差、呕吐、嗜睡）	2.13	513	C6DC 0.33，3-MGA 480.6，3-羟基异戊酸510.2	c.145-2A>G，c.590G>A, （p.C197Y）	家长放弃，3月龄死亡
5	女	8月龄	5月龄	是	无	急性期（呕吐、嗜睡、抽搐）	2.21	560	C6DC 0.08，3-MGA 250.1，3-羟基异戊酸450.1，甲状腺功能减退	未做	家长放弃，8月龄死亡
6	女	无	1月龄	是	无	未发病	2.02	86	C6DC 0.04，3-MGA 40.2，3-羟基异戊酸58.9，乳酸、血氨、血糖正常	c.697C>T（p.H233Y）纯合	现1岁，规律随访中，未发病

3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症临床特点及基因变异分析

Clinical and genetic analysis of children with 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency

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